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Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke.

Published version
Peer-reviewed

Type

Article

Change log

Abstract

Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10-4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.

Description

Funder: NIHR Cambridge Biomedical Research Centre

Keywords

Atrial Fibrillation, Blood Proteins, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Proteome, Risk Factors, Stroke

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
British Heart Foundation (RG/16/4/32218)
Medical Research Council (MR/S003746/1)
British Heart Foundation (RG/18/13/33946)
Wellcome Trust (204623/Z/16/Z)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Department of Health (via National Institute for Health Research (NIHR)) (NIHR BTRU-2014-10024)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
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